Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction

Maniratanachote, Rawiwan; Shibata, Ayaka; Kaneko, Shuichi; Yamamori, Ikuo; Wakasugi, Takanobu; Sawazaki, Takeshi; Katoh, Kanefusa; Tokudome, Shogo; Nakajima, Miki; Yokoi, Tsuyoshi

doi:10.1016/j.tox.2005.07.012

Cited by 25 publications

(14 citation statements)

References 32 publications

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“…This hepatic enzyme correlated with serum ALT and AST levels at baseline and returned to normal during follow-up. Of note, autoantibodies to this protein have previously been reported in patients with troglitazone hepatotoxicity (105). In addition, elevations in apolipoprotein E, an abundant lipoprotein of triglyceride rich chylomicrons, had the greatest ability to distinguish DILI patients from controls.…”

Section: Serum Proteomicsmentioning

confidence: 92%

Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives

2014

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Idiosyncratic drug-induced liver injury (DILI) is a rare disease that develops independently of drug dose, or route or duration, of administration. Furthermore, idiosyncratic DILI is not a single disease entity, but rather a spectrum of rare diseases with varying clinical, histologic, and laboratory features. The pathogenesis of DILI is not fully understood. Standardization of the DILI nomenclature and methods to assess causality, along with the information provided by the LiverTox website, will harmonize and accelerate DILI research. Studies of new serum biomarkers such as glutamate dehydrogenase, high-mobility group box-1 protein, and microRNA-122 could provide information for use in diagnosis and prognosis, and provide important insights into mechanisms of DILI pathogenesis. Single nucleotide polymorphisms in the HLA region have been associated idiosyncratic hepatotoxicity attributed to flucloxacillin, ximelagatran, lapatanib, and amoxicillin- clavulanate. However, genome-wide association studies of pooled cases have not associated any genetic factors with idiosyncratic DILI. Whole-genome and whole-exome sequencing analyses are underway to study DILI cases attributed to a single medication. Serum proteomic, transcriptome, and metabolome, along with intestinal microbiome, analyses will increase our understanding of the mechanisms of this disorder. Further improvements to in vitro and in vivo test systems should advance our understanding of the causes, risk factors, and mechanisms of idiosyncratic DILI.

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Section: Serum Proteomicsmentioning

confidence: 92%

Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives

2014

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“…Studies to clarify the possible involvement of autoantibodies in drug-induced hepatitis are limited because the appearance of autoantibodies can usually be seen only in humans. We recently reported that aldolase B, which is an enzyme predominantly localized in the liver and kidney (Penhoet et al 1966), was detected as an autoantigen that reacted with antibodies in the sera from two patients with type II diabetes mellitus and troglitazone-induced liver dysfunction (Maniratanachote et al 2005b). The titer of antialdolase B remained high for several weeks after stopping troglitazone administration.…”

Section: Hypersensitivity Reaction Associated With Troglitazone Hepatmentioning

confidence: 98%

“…However, autoantibodies to aldolase B were also detected in the sera of patients with chronic hepatitis as well as liver cirrhosis (Brown et al 1987;Maniratanachote et al 2005b). There are several reactive metabolites generated by troglitazone (Fig.…”

Section: Hypersensitivity Reaction Associated With Troglitazone Hepatmentioning

confidence: 99%

Troglitazone

Yokoi

2009

Handbook of Experimental Pharmacology

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Troglitazone was the first thiazolidinedione antidiabetic agent approved for clinical use in 1997, but it was withdrawn from the market in 2000 due to serious idiosyncratic hepatotoxicity. Troglitazone contains the structure of a unique chroman ring of vitamin E, and this structure has the potential to undergo metabolic biotransformation to form quinone metabolites, phenoxy radical intermediate, and epoxide species. Although troglitazone has been shown to induce apoptosis in various hepatic and nonhepatic cells, the involvement of reactive metabolites in the troglitazone cytotoxicity is controversial. Numerous toxicological tests, both in vivo and in vitro, have been used to try to predict the toxicity, but no direct mechanism has been demonstrated that can explain the hepatotoxicity that occurred in some individuals. This chapter summarizes the proposed mechanisms of troglitazone hepatotoxicity based in vivo and in vitro studies. Many factors have been proposed to contribute to the mechanism underlying this idiosyncratic toxicity.

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“…There may be many examples of immunemediated IDRs that have been misclassified because of this characteristic. One example is troglitazone-induced hepatotoxicity, which is classed as representing metabolic idiosyncrasy, but recently, it has been noted to be associated with autoantibodies (38). Another possibility is that troglitazone-induced hepatotoxicity involves mitochondrial damage.…”

Section: Nonimmune Mechanismsmentioning

confidence: 99%

Idiosyncratic Drug Reactions: Past, Present, and Future

Uetrecht

2007

Chem. Res. Toxicol.

238

190

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Although the major working hypothesis for the mechanism of idiosyncratic drug reactions (IDRs), the hapten hypothesis, has not changed since 1987, several hypotheses have been added, for example, the danger hypothesis and the pharmaceutical interaction hypothesis. Genetic studies have found that several IDRs are linked to specific HLA genes, providing additional evidence that they are immune-mediated. Evidence that most IDRs are caused by reactive metabolites has led pharmaceutical companies to avoid drug candidates that form significant amounts of reactive metabolites; however, at least one IDR, ximelagatran-induced liver toxicity, does not appear to be caused by a reactive metabolite. It is possible that there are biomarkers such as those related to cell stress that would predict that a drug candidate would cause a significant incidence of IDRs; however, there has been no systematic study of the changes in gene expression induced by drugs known to cause IDRs. A major impediment to the study of the mechanisms of IDRs is the paucity of valid animal models, and if we had a better mechanistic understanding, it should be easier to develop such models. There is growing evidence that these adverse reactions are more varied and complex than previously recognized, and it is unlikely that a quick fix will be achieved. However, IDRs are an important cause of patient morbidity and mortality and markedly increase the uncertainty of drug development; therefore, continued basic research in this area is essential.

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Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction

Cited by 25 publications

References 32 publications

Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives

Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives

Troglitazone

Idiosyncratic Drug Reactions: Past, Present, and Future

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